Penicillin derivatives

ABSTRACT

This invention relates to new penicillin derivatives and methods for preparing the same, said derivatives having the structure   WHEREIN Z is hydrogen, lower alkyl or a salt forming ion and R is aryl, substituted aryl, lower alkyl or cycloalkyl. These compounds are useful as antibacterial agents.

United States Patent Lee [ 51 May 27, 1975 PENICILLIN DERIVATIVES [75] Inventor: Bong Kuk Lee, Old Bridge, NJ.

[73] Assignee: E. R. Squibb & Sons, lnc.,

Princeton, NJ.

[22] Filed: May 30, 1972 [21] Appl. No.1 258,028

[52] U.S. Cl 260/239.1; 424/271 [51] Int. Cl C07d 99/16 [58] Field of Search 260/2391 [56] References Cited UNITED STATES PATENTS 3,230,214 l/l966 Fosker et a]. 260/239.l

Primary ExaminerNicholas S. Rizzo Attorney, Agent, or FirmLawrence S. Levinson; Merle J. Smith; Stephen B. Davis [57] ABSTRACT This invention relates to new penicillin derivatives and methods for preparing the same, said derivatives having the structure u H3 CH-C-NH N CH3 {f 6 cooz r i and 0 S C ll CH-C-NH/ N NH 0 'COOZ wherein Z is hydrogen, lower alkyl or a salt forming ion and R is aryl, substituted aryl, lower alkyl or cycloalkyl. These compounds are useful as antibacterial agents.

3 Claims, N0 Drawings PENICILLIN DERIVATIVES This invention relates to new penicillin derivatives of y the formula and CH3 ll -f.

In 'fH-C-NH' /7 N 3 :11 O1 COOZ l R The lower alkyl groups represented by the above R groups include straight or branched chain aliphatic hydrocarbon radicals having up to seven carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, heptyl, and the like. The lower alkyl groups can include as substituents any of the aryl groups mentioned below as well as halogen (Cl, Br, I or F).

The term aryl includes monocyclic or bicyclic monovalent aromatic ring systems such as phenyl or naphthyl. These aryl radicals can include as substituents at the ortho-position halogen, hydroxy, alkanoic acid, lower alkoxy, amido or any of the alkyl groups mentioned hereinbefore.

' For example, aryl radicals and substituted aryl radicals contemplated herein include, but are not limited to,,the following:

OH u 7 CO H I and ocH 3 The term cycloalkyl includes monocyclic carbocyclic radicals having from 3 to about 6 carbons such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The compounds of Formula II can be prepared by reacting a compound of the structure with an aldehyde of the structure RCH to form compounds of the structure In carrying out the above reaction, the reaction of compound IV with the aldehyde V is preferably carried out in an aqueous media such as in a mixture of water with a lower alkanol such as methanol, ethanol or npropanol, or ketones such as methylethyl ketone or methyl isobutyl ketone. The reaction may be carried at temperatures ranging from about 0 to about 40C. Compound IV is employed in a ratio to Compound V within the range of from about 1:1 to about 1:3, preferably from about 1:1 to about 121.5 and optimally at about 111.1. Compounds of formula II can also be prepared by a compound of the formula VII @cu cooz with an aldehyde of formula V to form a compound of the formula VIII and thereafter reacting VIII with an acid halide compound of the structure of formulatructure IX "xco alkyl to form a mixed anhydride of the structure which is reacted with 6-APA (i.e. 6-amino penicillanic acid) or an ester or salt thereof to form the formula 11 compounds.

The reaction of Compound VII with the aldehyde (V) is carried out in the presence of an aqueousalcoholic solvent, such as a mixture of water and methanol, at temperatures ranging from ambient temperature to the boiling point of the solvent. Compound VII can be employed in a molar ratio to the aldehyde (V) within the range of from about 1:1 to about 1:3 and preferably from about 1:1 to about 1:1.5.

The reaction of compounds VIII and IX is carried out in a mixture of solvents such as acetone, dioxane and lutidine at temperatures ranging from about to about 20C and preferably from about -10 to about 10C, employing a molar ratio of IXzVlII within the range of from about 1:1 to about 3:1 preferably 1.1:1 to 1.5:1.

The reaction of the mixed anhydride X with 6-APA is carried out in an aqueous solvent such as aqueous sodium bicarbonate at a temperature with the range of from about to about 5C and preferably from about 5 to about 0C employing a molar ratio of XzXl within the range of from about 120.8 to about 2:1 and preferably from about 1.1:1 to about 1.521.

O I ll 3 3 CH-C-N'H I I A CH NH N I gl cooz 1 III R The above reduction can be carried out in water or aqueous solvents, such as aqueous potassium phosphate, at temperatrues ranging from about 0 to about 40C and preferably from about 10 to about 20C employing a molar ratio of Compound'll to reducing agent within the range from about 1:2 to about 1:10 and preferably from about 1:4 to about 1:6.

Alternatively, the formula III compounds can be prepared by forming compounds of formula VllI above, reducing the formula VIII compound by reacting it with any of the aforementioned reducing agents to form a compound of the formula and thereafter reacting XII with an acid halide of structure IX to form the mixed anhydide of formula XIII.

which can be reacted with 6-APA (formula XI) to form the formula III compounds.

It will be appreciated that essentially the same reaction conditions as set out with respect to the reaction of Compounds VIII, IX, X and XI, apply here as well.

The starting materials of structure IV are prepared by coupling a compound of the structure XIV @cH-cooz with a 6-APA moiety, that is with XI NH 3 CH l CH N 3 cooz according to known techniques.

Examples of aldehydes which can be employed herein as starting materials include, but are not limited to, the following l and OCH C H CHO C H CHO CHO The products of this invention form salts which are also part of the invention. Basic salts form with the acid moiety as discussed above in connection with the symbol Z. Acid addition salts also form with the a-amino nitrogen. Such acid salts include, for example, inorganic salts such as thehydrohalides, e.g;, hydrobromide,- hydrochloride, hydroiodide, sulfate, nitrate,

phosphate, borate, etc., and organic salts such as acetate, oxalate, tartrate, malate, citrate, succinate, benzoate, ascorbate, methanesulfonate and the like. lt is frequently convenient to isolate and purify the product by forming a soluble or insoluble salt, as desired, then regenerating ,the free compound, by neutralization, .for

example. 7 v

. The compounds of this invention have abroad spectrum of antibacterial activity against both gram positive and gram negative organisms such asStaphylocobcus aureus, Salmonella schottmuielleri, Pseudomonas aeruginosa, Proteus vulgaris, Escherichia coliand Streptococcus pyrogenes. They may be used as antibacterial agents in a prophylactic manner, e.g., in cleaningordisinfecting compositions, or otherwise to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar; topenicillin G and other penicillins and cephalosporins. Forv example, a compound of Formula I or a physioilogically acceptable salt thereof may be used in variousanimalspecies in an amount of about 0.1 to 100 mg/kg. daily, orally or parenterally, in single or two to fourqdi v-ided doses to treat infections of bacterial origin. By -way of illustration the PD orally in mice in a, single administration is 1.3 mg./kg. against Streptococcus, 8.6 mg./kg. against Proteus and 11,8 mg./l g. against Salmonella, respectively. Up to about 600 mg. ofqacompound of Formula I or a salt thereof may be incorporated in an oral dosage form such as tablets, capsules or-elixirs, or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice. In cleaning or disinfecting compositions, e.g., in barns or dairy equipment, a concentration of; about 0.01 to 1% by weight of such compounds admixed with, suspended or dissolved in conventional inert .dry or aqueous carriers for application by washing orspraying may be used.

The following examples are illustrative of the invention. All temperatures are on the Centigrade scale.

EXAMPLE 1 6-[ 2-phenyl-2-[ 2-hydroxyll -naphthyl )methylene]- amino]acetamido]-3 ,3-dimethyl-7-oxo-4-thia- 1 azabicyclo[3.2.0 ]heptene-Z-carboxylic acid, sodium salt A. Na salt of phenylacetamido]penicillanic acid 50 The sodium salt of 6-[2-amino-2-phenylacetamide]- penicillanic acid is formed by dissolving 140 mg (4 millimoles) of 6-[2-amino- Z-phenylacetamido]phenicillanic acid and 336 mg (4 millimoles) of NaHCO in a mixture of 30 ml of H 0 5 and 350 ml of methanol.

6-[2-phenyl-2-[ 2-hydroxyl naphthyl)methylene]amino]-acetamido]-3,3-dimethyl- 7-oxo-4-thia-l-azabicyclo-[3.2.0]heptene-Z-carboxylic acid, sodium salt 60 712.4 mg (4.2 millimoles) of 2-hydroxy-lnaphthaldehyde is added to the'sodium salt solution prepared in A, and the reaction mixture is stirred for l 8 hours at about 10. Methanol is removed at 'less'than 10 in vacuo, and the remaining aqueous solution ly- 65 ophilized to yield the title compound.

a EXAMPLE 2 6-[2-phenyl-2- [[(2-hydroxy-l-naphthyl)methyl]- 6-[2-amino-2- '7 8 amino]acetamido]-3,3-dimethyl-7-oxo-4-thia-l- Table I azabicyclo[3.2.0]heptane-2-carboxylic acid, sodium salt g p Column Column 1,998 mg (3.6 millimoles) of the product of Examplb l is dissolved in 150 ml of potassium phosphate buffer 5 0.05 M, pH 6), and to this solution is added 455 mg AldehydeiR" CH0) Pmduct (12 millimoles) of NaBl-L, dissolved in 15 mil-1 0, CH0 dropwise, for 1 hour with vigorous stirring in ice bath. The reaction mixture is acidified to pH 3 with l N HCl, 4 as in column A and the product isolated by filtration and washed with cold water. The foregoing product and excess NaHCO are dissolved in a mixture of 10 ml H 0 and 100 m1 methanol. The methanol is removed in vacuo at a temperature below 10C, and the aqueous portion lyophilized to yield the title compound. C80

'EXAMPLE3 5 q 6-[ 2-phenyl-2-[ 2-hydroxyl naphthyl)methylene]amino]-acetamido]-3,3-dimethyl- 7-oxo-4-thia-1-azabicyclo[3,2,0]-heptane-2-carboxylic acid, sodium salt A suspension of the sodium salt of D-2-amino-2- CHO phenylacetic acid, 1.75 g (10 millimoles), and 2-hydroxy-l-naphthaldehyde, 3.44 g (20 millimoles), F in a mixture of ethanol (250 ml) and methanol (20 ml) is refluxed for 2 hours. The mixture is then evaporated under reduced pressure and the residue washed with ether and recrystallized from ethanol to give the sodium salt of phenyl-[[(2-hydroxy-l-naphthyl)rnethylene[amino[acetic acid.

2.63 g (8 millimoles) of the N-protected amino acid is dissolved in a mixture of dry acetone (100 ml), dioxane 25 ml) and 2,6-lutidine 1.35 ml). The solution is 7 rapidly chilled to -5, treated with ethyl chlorocarbonate O.955 mg (0.84 ml, 8.8 millimoles) and stirred at 0 for 10 minutes, during which lutidine hydrochloride is precipitated and the mixed anhydride formed in solution. The suspension is then cooled to and stirred vigorously while an ice-cold solution of '6-APA 1,305 mg. (6.1 millimoles) in 3% aqueous sodium bicarbonate (28 ml.) is added as rapidly as possible, the temperature of the mixture never being allowed to rise above 0. The resulting solution is stirred for 30 minutes at 0 and then for a further 30 minutes without external cooling. It is then extracted with ether (3 X 150 ml.), only the aqueous phase being retained. The latter is brought to pH 2 by addition of dilute hydrochloric acid and rapidly extracted with ether (100 ml. in 3 portions). These second ether extracts, containing the N- 9 C H CH0 protected penicillin are washed with water 10 ml.) and 3 7 then extracted with sufficient 3% sodium bicarbonate to give a neutral aqueous phase, which is separated and evaporated at low temperature and pressure. The resil0 CH due is shown, by paper chromatography of a small portion, to contain the sodium salt of the penicillin of the b t'tl a ove 1 e 11 Z 3 m as in colmm A EXAMPLES 4 to 12 The procedure described in Example 1 is repeated with the exception that the aldehydes set out below in Table 1, column A are employed, to thereby form the CH0 products set out in column B of Table I. 12

u I 5 3. I c 0 NH- 3 EXAMPLES 13 r 21 I N g Employing the procedure descrlbed in Example 2, ll 4') OOZ but substituting as the starting material, the products of 13 0 Examples 4 to 12, the products set out in Table ll below R are obtained.

9 l Table II EXAMPLES 22 to 30 0 Employing the procedure 0f Example 3, but substi- CH tutingthe startingmaterialsei outin columnAofTable C NH S III below, the product shown in column B thereof is ob- Cu CH3 5 tained. I

| N Table III cooz CH2 Starting Material Product I R @cln-wooz ExamEle No. R CH I R Ti 3 13 O @cH-ami S v 3 N cooz u A O CH l R Column Column Example No. A Z B F 22 I K as per 15 w column A 40 I r 23 n v no u F n I l7 OCH I II I 26 2o a ll I! 27 -c H c H Table III Continued Column Column Example No. A Z B R R Z 28 -C I' I Ne n 29 P K I u 30 Na u What is claimed is: 1. A compound of the formula CHCN l H \i .v 3 (1H C002 R 3. A compound in accordance with claim 2 wherein Z is Na.

UNITED sTATEs PATENT AND TRADEMARK OFFICE @ERTEFICATE 0F CGRRECTION PATENTNO. 3 5,140 DATED May 27,

INVENTOR(S) I Bong Kuk Lee It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: 0 O) H ll q Col. 1, formula II, "?HC-NH" should read -CH-CNH-.

N H CH it Col. 2, lines 64, 65 and 66, the sentence beginning "Compounds of formula II can also be prepared by a compound of the formula" should start a new paragraph and should read Compounds of formula II can also be prepared by reacting a compound of the formula.

Col. 3, line 12, "of formulatructure" should be cancelled.

Col. 6, line 50, "phenylacetamide" should read -phenylacetamido--a a C01, 6, line 55, -B. should be inserted at the beginning of the linen Col 7, line 4, "Examplb" should read EXample-.

a Col. 7, line 30, "[amino[acetic" should read -]amino]acetic- Col. 10, line 30, "Z" appearing between "Column A" and "Column B" should appear under "Column A" fiigned and grated this ninth Day Of September 1975 [SEAL] A ttes t:

RUTH C. MSON C. MARSHALL DANN Arresting Officer Commissioner ufParems and Trademarks 

1. A COMPOUND OF THE FORMULA
 2. A compound in accordance with claim 1 of the formula
 3. A compound in accordance with claim 2 wherein Z is Na. 